DESCRIPTION (provided by the investigator): Experimental and epidemiological evidence suggests that the relationship between prenatal smoking and intrauterine growth restriction (IUGR) is causal, yet the mechanism by which prenatal tobacco smoke exposure causes IUGR remains poorly defined. A plausible but, as yet, unstudied mechanism is intrauterine exposure to tobacco smoke components may prevent normal fetal programming through the hypomethylation of DNA leading to sub-optimal growth and development, which subsequently manifests as IUGR. A better understanding of the biological mechanism by which smoking causes IUGR could improve our ability to formulate more effective, targeted, and smart intervention measures. Study Objectives: The present study aims to evaluate the hypothesis that cigarette smoke exposure during pregnancy results in aberrant DNA methylation in hematopoietic stem cells in the feto-placental circulation. This epigenetic response to suboptimal uterine conditions is manifested in offspring as IUGR. We further hypothesize that cigarette smoke exposure will decrease stem cell numbers (normalized to feto-placental blood volume) as they may be more sensitive to adverse uterine conditions. Methods: The hypotheses will be tested using a case-control design involving small (SGA) and appropriate (AGA) for gestational age infants born at Tampa General Hospital. Only non-malformed singleton infants from otherwise normal pregnancies are eligible for the study. Umbilical cord blood collected as part of a larger study at Tampa General Hospital will be analyzed for concentration of red blood cell folate, cotinine, and stem cells as well as for the amount of global genomic DNA methylation. Regression models that control for potential confounders such as serum folate, maternal age, parity, race/ethnicity, body mass index status, previous IUGR/fetal death, and fetal gender will be developed to address the aims and objectives of the study. Implications of research: This study's interdisciplinary approach has the potential to provide evidence that could change our current thinking of tobacco smoke patho-physiology as epigenetic modifications have not been considered as a possible mechanism by which IUGR or other adverse pregnancy outcomes related to tobacco smoke exposure manifest. Finally, it may lead to the development of new interventions to reduce the impact of prenatal smoke exposure on the developing fetus and a more efficient detection of hematopoietic stem cells unsuitable for transplant, thus improving outcomes and preventing storage of sub-optimal umbilical cord blood samples.